BES2003 Symposia The Adipocyte as an Endocrine Organ (4 abstracts)
Reduced intra-adipose glucocorticoid regeneration: A novel adaptive response to, and therapy for, the metabolic syndrome
NM Morton 1 , JM Paterson 2 , H Masuzaki 3 , MC Holmes 4 , B Staels 5 , C Fievet 5 , BR Walker 1 , J Flier 3 , JJ Mullins 2 & JR Seckl 1
1Endocrinology Unit, University of Edinburgh, UK; 2Molecular Physiology, University of Edinburgh, UK; 3Division of Endocrinology and Metabolism and Medicine, Beth Israel Deaconess and Harvard Medical School, USA; 4Clinical Neurosciences, University of Edinburgh, UK; 5Department d' Atherosclerose, Pasteur Institut de Lille and Universite de Lille II, France.
Metabolic Syndrome (visceral obesity, insulin resistance, type2 diabetes) resembles Cushing's syndrome, but lacks elevated circulating cortisol levels. This has engendered the hypothesis that excessive local glucocorticoid regeneration, resulting from elevated adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) underlies the Metabolic Syndrome. We report that 11beta-HSD-1 nullizygosity (11beta-HSD-1-/-) reduced intra-adipose corticosterone levels and increased adipocyte insulin sensitivity. With high fat (HF) feeding, 11beta-HSD-1-/- mice (in both obesity-prone and obesity-resistant strains) exhibited reduced visceral fat accumulation, selectively redistributing fat to 'metabolically safer' peripheral depots in association with elevated PPARgamma expression and improved glycemic, lipid and adipose gene expression profiles. On the obesity-prone background, 11beta-HSD-1-/- mice gained less weight despite consuming more calories. Intriguingly, wild type mice down-regulated 11beta-HSD-1 in white and brown fat in response to HF feeding, an effect that was exaggerated in obesity-resistant mice. These data show that adipose 11beta-HSD-1 deficiency contributes to a protective metabolic phenotype. Down-regulation of adipose 11beta-HSD-1 in response to HF represents a novel mechanism, attenuated in the obesity-prone, that counteracts central adiposity and its metabolic consequences.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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